MINIMAL INVASIVE TREATMENT OF PENILE CURVATURE
Prof. Dr. Med. Semir Al Samarrai
Penile Curvature can be congenital or acquired.Acquired curvature is secondary due to La Peyronie’s disease.
Credit for the first description of Peyronie’s disease is given to Francois Gigot de la Peyronie in 1743. Peyronie’s disease is also known as induratio plastica of the penis. In most patients, reassurance is sufficient and necessity. Fortunately, only a minority of patients will have deformity that precludes them from having sexual intercourse. Most of the patients with Peyronie’s disease do not require surgery. Surgery, at best, can be viewed as palliation for the mechanical effects of Peyronie’s disease and erectile dysfunction. Peyronie’s disease was associated with Dupuytren disease. Dupuytren disease has a familial pattern known to be transmitted in an autosomal dominant pattern. Thirty percent (30%) to forty percent (40%) of men with Peyronie’s disease will also have Dupuytren disease (Nyberg et al, 1982; Ralf et al, 1997).
Other associated fibrotic conditions are contracture of the plantar fascia (Ledderhose Disease) and tympanosclerosis. Peyronie’s disease is also reported to occur in patients after external trauma to the penis (e.g., seat belt injuries). The aetiology of Peyronie’s disease is unknown. However, an insult (repetitive microvascular injury or trauma to the penile fascia (tunica albuginea) is the most widely accepted hypothesis on the aetiology of the disease (3).Peyronie’s diseasestartswith an acute inflammatory process. The acute inflammation induce the proliferation of the penile fascia fibroblasts, some of which differentiate into myofibroblasts, with excessive deposition of collagen, persistence of fibrin and elastin fragmentation. A prolonged inflammatory response can result in the remodelling of the connective tissue of the penile fascia into a dense fibrotic plaque (3-5). These penile plaques formation can result in curvature which, if severe, may hinder vaginal penetration. The prevalence of PD is estimated at up to 7% among men in the general population, up to 8% of men with erectile dysfunction, and >20% of men with comorbidity. The most commonly associated comorbidities and risk factors are diabetes, hypertension, lipid abnormalities, ischaemic cardiopathy, erectile dysfunction, smoking, and excessive consumption of alcohol (1, 2, 6, 7).4% of patients with Dupuytren’s contracture reported Peyronie’s disease (8).
Peyronie’s disease can be a chronic and progressive disease.The phases of the disease can be distinguished (9).The first is the acute inflammatory phase, which may be associated with pain in the flaccid state or painful erections and manifestation of a ‘soft’ nodule/plaque and penile curvature. The second is the fibrotic phase with the formation of hard palpable plaques that can be calcified, which also result in disease stabilization. Spontaneous improvement is expected in 30-50% or stabilize in 47-67% of patients. Pain is present in 35-45% of patients during the early stage of the disease (7, 10, 11, 13). Pain tends to resolve with time in 90% of men, usually during the first 12 months after the onset of the disease (10, 11). In addition to physiological and functional alteration of the penis, affected men also suffer significant distress and 48% of men with this disease have mild or moderate depression (14).
The aim of the initial evaluation is to provide information of the presenting symptoms and their duration (erectile pain, palpable nodules, curvature, length, rigidity and girth of penis and erectile function status.
Major attention should be given to whether the disease is still active, as this will influence medical treatment or the timing of surgery. Patients who are still likely to have an active disease are those with short symptom duration, pain during erection, or a recent change in penile curvature. It is often difficult to evaluate the end of the inflammatory phase but resolution of pain and stability of the curvature for at least 3 months are well accepted criteria of disease stabilization and patients referral for surgery intervention when indicated (10). The examination should start with a routine genitourinary assessment, which is then extended to the hands and feet for detecting possible Dupuytren’s contracture or Ledderhose scarring of the plantar fascia (11). Penile examination consists generally of a palpable node or plaque. The whole of the penis should be examined. It is recommended to measure the penis dorsally from the base to the tip of the glans wile at full stretch (11). Plaque size is measured in the erect penis. Measurement at length during erection is important because it impacts directly on treatment decisions (16). Girth-related changes are often self-reported by the patients.
Erectile function can be assessed using validated instruments such as the International Index of Erectile Function (IIEF) (17).
Erectiledysfunction is quite common (>50%) in patients with Peyronie’s disease but it is important to define if pre-dated or post-dated Peyronie’s disease onset. It is mainly due to penile vascular disease (7, 12). The presence of erectile dysfunction may impact on the treatment strategy (18).
Ultrasound (US) measurement of the plaque’s size is inaccurate and operator dependent and it is not recommended in everyday clinical practice (19). Color-Doppler-US may be required for the assessment of vascular parameters (18). An objective assessment of penile curvature with an erection is mandatory. This can be obtained by a home (self) photography of natural erection (preferably) or using a vacuum assisted erection test or an intracavernosal injection using vasoactive agents (15).
Minimal Invasive Treatments:
Conservative treatment of Peyronie’s disease is primarily focused on patients in the early stage of the disease, when symptoms are present and the plaque is not fibrotic or calcified (11, 20).
In this context, several options have been suggested, including oral pharmacotherapy, intralesional injection therapy and other topical treatments.
- Oral Therapy:
a. Vitamin E:
Vitamin E (tocopherol, a fat soluble compound that acts as natural antioxidant to reduce the number of oxygen-free radicals produced in energy metabolism) is commonly used as potential treatment, but a double-blind, placebo-controlled crossover study failed to show a significant effect on penile deformity or plaque size (21).
b. Potassium para-aminobenzoate (Potaba)
This therapy is thought to exert an antifibrotic effect an increase in oxygen uptake by the tissues, a rise in the secretion of glycosaminoglycans, and an enhancement of the activity of monoamine oxidase (22). It is role in treatment of this disease is due to improvement in penile curvature, penile plaque size, and penile pain during erection (23). The optimal dose and duration of this therapy is (12g/day for 12 months).
Tomoxifen is a non-steroidal aestrogen receptor anatagonist. Its proposed mechanism of action is Peyronie’s disease involves the modulation of (TGF–β-1) secretion by fibroblasts. 20 mg twice a day for 3 months improved penile pain, penile curvature, and reduced the size of penile plaque (24).
Colchicine is a medicine often used to treat acute attacks of gout. It has been introduced into the treatment of Peyronie’s disease on the basis of its anti-inflammatory effect (25).
The efficacy of these Acetyl-esters of Carnitine has been suggested that it can reduce intracellular calcium levels in endothelial cells (26). This may eventually suppress fibroblast proliferation and collagen production, thus reducing penile fibrosis.
Finally, the combination of intralesional Verapamil (10 mg weekly for 10 weeks) with L-Carnitine (2 g/day for 3 months) significantly reduced penile curvature, plaque size and disease progression compared to intralesional verapamil combined with tomoxifen (40 mg/day for 3 months) (27).
This substance is a non-specific phosphodiesterase manipulator which down regulates TGF–β-1and increases fibrinolytic activity (28). Moreover, an increase of nitric oxide levels may be effective in preventing progression of Peyronie’s disease or reversing fibrosis (29). 400 mg Pentoxifylline three times a day for 6 months improve penile curvature and the findings on Ultrasound investigations of the plaque (29).
g. Phosphodiesterase type 5 inhibitors:
This substance can reduce the collagen/smooth muscle and collagen 3/1 ratio and increase the cryptotic index in the Peyronie’s disease-like plaque (30).
2. Intralesional Treatment:
a. Clostridial Collagenase:
Clostridial Collagenase is a chromatographically purified bacterial enzyme that selectively attacks collagen, which is known to be the primary component of the Peyronie’s disease plaque (31-33).
After CCH treatment, a significantly greater percentage ofpatients (36%) showed a positive response in penile curvature deformity or plaque size or number (36).
The most rigorous CCH treatment trial to date includes two phase 3 double-blind RCTs (Randomized Controlled Trials) involving 832 patients from 64 sites across the USA and Australia treated and followed over 52 weeks (38). CCH-treated patients showed a mean 34% improvement in penile curvature deformity. Overall, studies have generally found mean improvements in penile curvature of 15-20ᵒ with CCH treatments (36, 37, 38).
Interferon α-2b has been shown to decrease fibroblast proliferation, extracellular matrix production and collagen production from fibroblasts and improved the wound healing process from Peyronie’s disease plaques.
Intravesical injections for 12 weeks significantly improved penile curvature, plaque size and density, and pain compared to placebo (34, 35). They can be effectively treated with non-steroidal-anti-inflammatory drugs before interferon injections.
The minimal invasive treatments with the highest level of evidence supporting effectiveness in improvement of penile curvature deformity include intralesional injections using IFN α-2b or Collagenase Clostridium Histolyticum (CCH).
Prof. Dr. Semir Ahmad Salim Al Samarrai
Director of Professor Al Samarrai Medical Center
(Urology, Urological Oncology, Andrology, Male Infertility)
Dubai Healthcare City
Tel no.: +97144233669
1. Lindsay MB, Schain DM, Grambsch P, et al. The incidence of Peyronie’s disease in Rochester, Minnesota, 1950 through 1984. J Urol 1991 Oct;146(4):1007-9.
2. Sommer F, Schwarzer U, Wassmer G, et al. Epidemiology of Peyronie’s disease. Int J Impot Res 2002 Oct;14(5):379-83.
3. Devine CJ Jr, Somers KD, Jordan SG, et al. Proposal: trauma as the cause of the Peyronie’s lesion. J Urol 1997 Jan;157:285-90.
4. Jarow JP, Lowe FC. Penile trauma: an etiologic factor in Peyronie’s disease and erectile dysfunction. J Urol 1997 Oct;158(4):1388-90.
5. Gonzales-Cadavid NF,Rajfer J. Mechanisms of Disease: new insights into the cellular and molecular pathology of Peyronie’s disease. Nat Clin Pract Urol 2005 Jun;2(6):291-7.
6. Rhoden EL, Riedner CE, Fuchs SC, et al. A cross-sectional study for the analysis of clinical, sexual and laboratory conditions associated to Peyronie’s disease. J Sex Med 2010 Apr;7(4 Pt 1):1529-37.
7. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 307 men with Peyronie’s disease. J Urol 2002 Sep;168(3):1075-9.
8. Carrieri MP, Serraino D, Palmiotto F, et al. A case-control study on risk factors for Peyronie’s disease in young men. J Sex Med 2007 Mar;4(2):485-90.
9. Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med 2010 Jul;7(7):2359-74.
10. Gelbard MK, Dorey F, James K. The natural history of Peyronie’s disease. J Urol 1990 Dec;144(6):1376-9.
11. Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie’s disease. J Urol 2006 Jun;175(6):2115-8;discussion 2118.
12. Bekos A, Arvaniti M, Hatzimouratidis K, et al. The natural history of Peyronie’s disease: an ultrasonography-based study. Eur Urol 2008 Mar;53(3):644-50.
13. Pryor JP, Ralph DJ. Clinical presentations of Peyronie’s disease. Int J Impot Res 2002;14:414-7.
14. Nelson CJ, Diblasio C, Kendirci M, et al. The chronology of depression and distress in men with Peyronie’s disease. J Sex Med 2008 Aug;5(8):1985-90.
15. Levine LA, Greenfield JM. Establishing a standardized evaluation of the man with Peyronie’s disease. Int J Impot Res 2003 Oct;15 Suppl 5:S103-12.
16. Greenfield JM, Lucas S, Levin LA. Factors affecting the loss of length associated with tunica albuginea plication for correction of penile curvature. J Urol 2006 Jan;175(1):238-41.
17. Rosen RC, Riey a, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997 Jun;49(6):822-30.
18. Kadioglu A, Tefekli A, Erol H, et al. Color Doppler ultrasound assessment of penile vascular system in men with Peyronie’s disease. Int J Impot Res 2000 Oct;12(5):263-7.
19. POrst H, Vardi Y, Akkus E, et al. Standards for clinical trials in male sexual dysfunctions. J Sex Med 2010 Jan;7(1 Pt 2):414-44.
20. Hellstorm WJ, Bivalacqua TJ. Peyronies’s disease: etiology, medical, and surgical therapy. J Androl 2000 May-June;21(3):347-54.
21. Pryor JP, Farell CF. Controlled clinical trial of Vitamin E in Peyronie’s disease. Prog Reprod Biol 1983;9:41-5.
22. Griffiths MR, Priestley GC. A comparison of morphoea and lichen sclerosus et atrophicus in vitro: the effects of para-aminobenzoate on skin fibroblasts. Acta Derm Venereol 1992;72(1):15-8.
23. Zarafonetis CJ, Horrax TM. Treatment of Peyronie’s disease with potassium para-aminobenzoate (potaba). J Urol 1959 Jun;81(6):770-2. [No abstract available]
24. Ralph DJ, Brooks MD, Bottazo GF, et al. The treatment of Peyronie’s disease with tamoxifn. Br J Urol 1992 Dec;70(6):648-51.
25. Kadioglu A, Tefekli A, Koksal T, et al. Treatment of Peyronie’s disease with oral colchicine: long-term results and predictive parameters of successful outcome. Int J Impot Res 2000 Jun;12(3):169-75.
26. Netticadan T, Yu L, Dhalla NS, Panagia V. Palmitoyl carnitine increases intracellular calcium in adult rat cardiomyocytes. J Mol Cell Crdiol 1999 Jul;31(7):1357-67.
27. Cavallini G, Biagiotti G, Koverech A, et al. Oral propionyl-l-carnitine and intraplaque verapamil in the therapy of advanced and resistant Peyronie’s disease. BJU Int 2002 Jun;89(9):895-900.
28. Shindel AW, Lin G, NIng H, et al. Pentoxifylline attenuates transforming growth factor-beta1-stimualted collagen deposition and elastogenesis in human tunica albuginea-derived fibroblasts part 1: impact on extracellular matrix. J Sex Med 2010 Jun;7(6):2077-85.
29. Brant WO, Dean RC, Lue TF. Treatment of Peyronie’s diseasewith oral pentoxifylline. Nat Clin Pract Urol 2006 Feb;3(2): 111-5; quiz 116.
30. Ferrini MG, Kovanecz I, Nolazco G, et al. Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie’s disease. BJU Int 2006 Mar;97(3):625-33.
31. Gelbard MK, James K, Riach P, et al. Collagenase versus placebo in the treatment of Peyronie’s disease; a double-blind study. J Urol 1993 Jan;149(1):56-8.
32. Ehrlic HP. Scar contracture: cellular and connective tissue aspects in Peyronie’s disease. J rol 1997 Jan;157(1):316-9.
33. Jordan GH. The use of intralesional clostridial collagenase injection therapy for Peyronie’s disease: a prospective, single-center, non-placebo-controlled study. J Sex Med 2008 Jan;5(1):180-7.
34. Kendirci M, Usta MF, Matern RV, et al. The impact of intralesional interferon alpha-2b injection therapy on penile hemodynamics in men with Peyronie’s disease. J Sex Med 2005 Sep;2(5):709-15.
35. Hellstrom WJ, Kendirci M, Matern R, et al. Singe-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2B for minimally invasive treatment for Peyronie’s disease. J Urol 2006 Jul;176(1):394-8.
36. Gelbard MK, James K, Riach P, Dorey F. Collagenase versus placebo in the treatment of Peyronie’s disease: a double-blind study. J URol 1993;149:56-8.
37. Gelbard M, Lipshultz LI, Tursi J, Smith T, Kaufman G, Levine LA. Phase 2b study of clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie’s disease. J Urol 2012;187:2268-74.
38. Gelbard M, Goldstein I, Hellstorm WJ et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie’s disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol 2013; 190:199-207.
Prof. Dr. SEMIR AHMED SALIM AL SAMARRAI
Professor Doctor of Medicine-Urosurgery, Andrology, and Male Infertility
Dubai Healthcare City, Dubai, United Arab Emirates.
Mailing Address: Dubai Healthcare City, Bldg. No. 64, Al Razi building, Block D,
2nd floor, Dubai, United Arab Emirates, PO box 13576